The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ATP-binding cassette (ABC) transporters superfamily, which functions as not only a transport but also a Cl- channel gated by protein kinase-dependent phosphorylation and cycles of ATP binding and hydrolysis. While the biophysical and pharmacological properties of the CFTR Cl- channels have been well characterized, the functional role of CFTR in the heart in the context of health and disease remains elusive. Recent clinical evidence points to a potential role of CFTR in heart failure (HF) but the exact functional and clinical significance of cardiac CFTR in myocardial hypertrophy and HF has not been studied. The long-term goal of our study is to determine the novel cardioprotective role of cardiac CFTR in cardiac hypertrophy and HF and to investigate the underlying molecular mechanisms. The short-term goal is to explore the functional and mechanistic bases of CFTR in the protection of cardiac myocytes against oxidative stress damage inflicted during myocardial hypertrophy and heart failure. To achieve these goals this proposal addresses the following specific aims: 1) to determine the functional role of CFTR in cardiac hypertrophy and failure through the demonstration of that targeted inactivation of CFTR gene causes a loss of compensatory response of cardiac function during the development of pathological myocardial hypertrophy and accelerate the progression of HF; 2) to determine whether CFTR is involved in redox regulation by demonstration of that a) CFTR is expressed on mitochondria, b) targeted inactivation of CFTR decreases mitochondrial concentration of - glutamyl-cysteinyl-glycine ([GSH]mito), and c) CFTR-mediated changes in [GSH]mito are closely coupled to regulation of mitochondrial function and cell viability under hypertrophy-induced oxidative stress. Experimental approaches will involve the use of CFTR knockout mouse, isolated working heart preparations, pressure-overload model of myocardial hypertrophy and HF, serial echocardiography, molecular biological and immunological techniques and mitochondrial GSH measurement and functional assays. The significance is that these studies will gain crucial evidence for the novel function of CFTR in protection of the heart against cardiac hypertrophy and failure and substantial knowledge on the novel mechanisms of redox regulation by CFTR-mediated mitochondrial GSH homeostasis, which will setup the stage for further understanding of the function and mechanism for the sarcolemmal and mitochondrial CFTR interactomes in the heart and pave a new path to the identification of novel therapeutic targets and thus translate these preclinical findings into clinical treatment of HF.